Target engagement of ginsenosides in mild cognitive impairment using mass spectrometry-based drug affinity responsive target stability

Zhu Zhu; Ruimei Li; Wei Qin; Hantao Zhang; Yao Cheng; Feiyan Chen; Cuihua Chen; Lin Chen; Yunan Zhao

doi:10.1016/j.jgr.2021.12.003

Target engagement of ginsenosides in mild cognitive impairment using mass spectrometry-based drug affinity responsive target stability

J Ginseng Res. 2022 Nov;46(6):750-758. doi: 10.1016/j.jgr.2021.12.003. Epub 2021 Dec 17.

Authors

Zhu Zhu¹, Ruimei Li¹, Wei Qin¹, Hantao Zhang², Yao Cheng¹, Feiyan Chen³, Cuihua Chen³, Lin Chen², Yunan Zhao¹

Affiliations

¹ Department of Pathology and Pathophysiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
² Department of Physiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
³ Research and Innovation Center, College of Traditional Chinese Medicine & Integrated Chinese and Western Medicine College, Nanjing University of Chinese Medicine, Nanjing, China.

Abstract

Background: Mild cognitive impairment (MCI) is a transitional condition between normality and dementia. Ginseng is known to have effects on attenuating cognitive deficits in neurogenerative diseases. Ginsenosides are the main bioactive component of ginseng, and their protein targets have not been fully understood. Furthermore, no thorough analysis is reported in ginsenoside-related protein targets in MCI.

Methods: The candidate protein targets of ginsenosides in brain tissues were identified by drug affinity responsive target stability (DARTS) coupled with label-free liquid chromatography-mass spectrometry (LC-MS) analysis. Network pharmacology approach was used to collect the therapeutic targets for MCI. Based on the above-mentioned overlapping targets, we built up a protein-protein interaction (PPI) network in STRING database and conducted gene ontology (GO) enrichment analysis. Finally, we assessed the effects of ginseng total saponins (GTS) and different ginsenosides on mitochondrial function by measuring the activity of the mitochondrial respiratory chain complex and performing molecular docking.

Results: We screened 2526 MCI-related protein targets by databases and 349 ginsenoside-related protein targets by DARTS. On the basis of these 81 overlapping genes, enrichment analysis showed the mitochondria played an important role in GTS-mediated MCI pharmacological process. Mitochondrial function analysis showed GTS, protopanaxatriol (PPT), and Rd increased the activities of complex I in a dose-dependent manner. Molecular docking also predicted the docking pockets between PPT or Rd and mitochondrial respiratory chain complex I.

Conclusion: This study indicated that ginsenosides might alleviate MCI by targeting respiratory chain complex I and regulating mitochondrial function, supporting ginseng's therapeutic application in cognitive deficits.

Keywords: Drug affinity responsive target stability (DARTS); Ginsenoside; Mild cognitive impairment; Mitochondria; Target engagement.